Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults

Abstract

Background:Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS).Methods:Eligible CHS participants were free of prevalent stroke and underwent quantification of 1298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-standard deviation increase in the log-2 transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and non-cardioembolic IS as well as proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation.Results:Of 2983 eligible participants, the mean age was 74.3 (± 4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal pro-brain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, P=2.08x10-08) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16-1.45, P=4.55x10-06) were independently associated with IS risk. These two associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident non-cardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction.Conclusions:In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and non-cardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.

Exploring the Plasma Proteome Networks: Unravelling Insights into Ischemic Stroke Pathophysiology

“…[22][23][24] The consistent associations of NTproBNP and MMP12 with IS risk in both racial subgroups suggest that these biomarkers transcend racial differences and remain informative predictors of stroke risk. 15 This finding highlights the potential of these biomarkers to contribute to inclusive stroke prevention strategies that are applicable to diverse populations. By demonstrating the consistent associations of NTproBNP and MMP12 with IS risk across sex and race subgroups, this study emphasizes the importance of personalized approaches in stroke risk assessments.…”

“…The evaluation of associations in subgroups defined by sex and race is a crucial aspect of the study on plasma proteomics and ischemic stroke risk. 15 The consistent associations of NTproBNP and MMP12 with IS risk across these subgroups underscore the robustness of these biomarkers in predicting stroke, irrespective of gender or race. The finding that NTproBNP and MMP12 are independently associated with IS risk in both men and women is significant.…”

“…The analysis of subtype-specific associations in the study provided valuable insights into the distinct protein signatures associated with cardioembolic and noncardioembolic IS. 15 By identifying these subtype-specific protein patterns, the study opens avenues for tailored preventive interventions and targeted therapies based on the underlying mechanisms of each stroke subtype. The identification of specific protein signatures associated with cardioembolic IS is particularly significant.…”

“…The study by Kalani et al, 15 marks a significant step forward in our understanding of the plasma proteomic landscape and its relevance to IS risk prediction. The identified biomarkers, NTproBNP and MMP12, hold promise as potential targets for therapeutic interventions and risk stratification in stroke.…”

“…14 These non-invasive tests could offer valuable insights into brain functionality. In a recent study conducted by Kalani et al,15 the relationship between the plasma proteome and IS risk was investigated using data from the Cardiovascular Health Study (CHS). The findings shed light on significant associations between specific plasma proteins and IS risk, presenting an opportunity for future advancements in stroke prevention and management.…”